Search

Objectives To evaluate the safety and efficacy of cidofovir for the treatment of double-stranded DNA (dsDNA) viral infections following allogeneic haematopoietic cell transplant (HCT). Methods This was a retrospective multicentre cohort study including adult HCT recipients who received ≥1 dose of IV-administered cidofovir for any dsDNA viral infection from 2006 to 2019. The objectives were to describe the rate of and risk factors for nephrotoxicity and virological response by the end of treatment (EOT). Results We included 165 patients from nine centres. Cidofovir was administered at 5 mg/kg/week (N = 115; 69.7%), 1 mg/kg/week (18; 10.9%), 3 mg/kg/week (12; 7.3%) or 1 mg/kg three times/week (11; 6.7%). Cidofovir was administered for adenovirus, cytomegalovirus (CMV) and BK virus infection in 75 (45.5%), 64 (38.8%) and 51 (30.9%) patients, respectively. Among 158 patients with renal function data at baseline and EOT, 40 (25.3%) developed nephrotoxicity. In multivariable analyses, age (OR 1.04; P = 0.05), weight (OR 1.05; P = 0.01), CMV infection (OR 3.6; P = 0.02), liposomal amphotericin B (OR 8.06; P = 0.05) and IV voriconazole/posaconazole (OR 13.0; P = 0.003) were predictors of nephrotoxicity. Creatinine concentration was significantly higher at EOT (1.16 ± 0.95 mg/dL) compared with baseline (0.91 ± 0.39 mg/dL; P Conclusions One in four HCT recipients treated with IV cidofovir developed largely reversible nephrotoxicity. Careful selection of patients and close follow-up of renal function may minimize toxicity.

Background Treatment of ganciclovir-resistant (GCV-R)/refractory cytomegalovirus (CMV) infections in blood/marrow transplant (BMT) and solid organ transplant (SOT) recipients remains suboptimal. Cidofovir (CDV), a nucleotide analogue with anti-CMV activity, is nephrotoxic and oculotoxic. Methods We retrospectively evaluated the outcomes of SOT and BMT patients with GCV-R/refractory CMV treated with CDV between 1/1/2008 and 12/31/2017. Data collected baseline demographics, CMV serostatus, clinical and virologic presentations and outcomes, UL97 and UL54 genotype mutations, drug toxicities, and cause of death. Descriptive statistics were used. Results 16 patients received CDV for treatment of CMV: six BMT and 10 SOT. Seven (47%) of the patients had high-risk donor/recipient serostatus: six (60%) SOT were D+/R-; one (16.7%) BMT was D-/R+. Median time to CMV DNAemia was 131 days post-transplant (IQR, 37.5-230.3). Proven tissue invasive disease was present in three patients (18.8%). Twelve (75%) had genotype testing; 10 (83.3%) of those had antiviral resistance mutations. While on CDV, six (37.5%) developed nephrotoxicity, and four (25%) developed uveitis (two had both uveitis and nephrotoxicity). Eight (50%) had failure to clear CMV DNAemia despite CDV treatment. Eight (50%) of the patients died; median time to death, after initiation of CDV, was 33.5 days [IQR22-988]. Conclusions In the absence of good therapeutic alternatives, CDV is used in GCV-R/refractory CMV infection. However, it is associated with a substantial risk of toxicity and failure to clear CMV DNAemia, highlighting the need for development of newer and less toxic therapies. The high mortality in this group of patients underscores the severity of illness in this population.

Background Patients with hematologic malignancies (HM) or hematopoietic stem cell transplant (HSCT) commonly receive broad-spectrum antimicrobials, often leading to the development of multidrug resistant organisms (MDRO). At our institution, rectal stool surveillance cultures (SSC) are done weekly on admitted adult patients with HMs or HSCT. The objective of this study is to determine the role of SSCs in predicting the development of a sterile site infection (StSI) with the same MDRO as identified in the SSC. Methods We retrospectively evaluated StSIs (blood, CSF, sputum/respiratory, pleural fluid, and urine) and SSC data from 242 adult patients admitted to the adult oncology ward at a large academic tertiary care center from 6/1/2017 to 2/28/2019. Demographics, SSC data, and StSIs in a 3-month period following the last SSC for each patient were collected from electronic medical records. SSCs were cultured on HardyCHROM ESBL™ media. MDRO similarity between SSC and StSI was determined by comparing susceptibility profiles. JMPÒ Pro 14.3.0 and RStudio were used for statistical analyses. Results Two hundred forty-two patients yielded 732 SSCs. We eliminated SSCs with incomplete (< 3 months of follow up) data. Thus, 579 SSCs were included in the analyses. 64% of patients were male. Leukemias (55.4%), lymphomas (21.9%), and multiple myeloma (10.3%) were the most common HMs. HSCT recipients comprised 50.4%. SSCs were positive for a MDRO in 251 cases (vancomycin-resistant enterococci, 52.2%; extended-spectrum beta-lactamase (ESBL) producing organisms, 22.2%; and carbapenamase producing organisms, 4.4%). There were 54 StSIs documented where the MDRO was the same as the SSC MDRO. The NPV of the SSC was 95.1% (95%CI 0.93,0.97). The positive likelihood ratio of the SSC was 2.5 (95%CI 2.07,3.02). Conclusion Our results suggest that a negative SSC is associated with a lower probability of identifying a StSI with an MDRO. Clinically, this can be useful in providing the opportunity to judiciously guide antimicrobial therapy, thereby avoiding the unnecessary usage of broad-spectrum antimicrobials when no MDRO is identified in the SSC. Disclosures All Authors: No reported disclosures

Background Establishing rapid diagnoses of invasive aspergillosis (IA) is a priority tests that detect galactomannan and β-d-glucan are available, but are technically cumbersome and rely on invasive sampling (blood or bronchoalveolar lavage). Methods We optimized a lateral flow dipstick assay using the galactofuranose-specific monoclonal antibody (mAb476), which recognizes urine antigens after Aspergillus fumigatus pulmonary infection in animals. Urine samples were obtained from a cohort of 78 subjects undergoing evaluation for suspected invasive fungal infections, and stored frozen until testing. Urine was processed by centrifugation through desalting columns and exposed to dipsticks. Reviewers blinded to clinical diagnoses graded results. Western blots were performed on urine samples from 2 subjects to characterize mAb476-reactive antigens. Results Per-patient sensitivity and specificity for diagnosis of proven or probable IA in the overall cohort was 80% (95% confidence interval [CI], 61.4%-92.3%) and 92% (95% CI, 74%-99%), respectively. In the subgroup with cancer, sensitivity was 89.5% (95% CI, 66.7%-98.7%) and specificity was 90.9% (95% CI, 58.7%-99.8%); among all others, sensitivity and specificity were 63.6% (95% CI, 30.8%-89.1%) and 92.9% (95% CI, 66.1%-99.8%), respectively. Eliminating lung transplant recipients with airway disease increased sensitivity in the noncancer cohort (85.7% [95% CI, 42.1%-99.6%]). Semiquantitative urine assay results correlated with serum galactomannan indices. Western blots demonstrated mAb476-reactive antigens in urine from cases, ranging between 26 kDa and 35 kDa in size. Conclusions Urine testing using mAb476 may be used as an aid to diagnose IA in high-risk patients.

In this study time-efficient size controlled synthesis of stable Pd nanoparticles was carried out using microwave heating method by the decomposition of palladium chloride with glucose in aqueous medium using poly(ethyleneglycol) as capping agent. The benefit of the synthesis is that it was achieved in only 20 s. The synthesized Pd nanoparticles were characterized by UV–Visible spectroscopy, transmission electron microscopy, X-ray diffraction, and particle size analysis. The relative rates of electro-oxidation of formic acid, methanol and ethanol measured by cyclic voltammetry showed that efficiency of Pd nanoparticles as catalyst followed the order: formic acid

An EDXRF set-up has been used to generate mechanistic information on the photolytic and physicochemical events leading to deposition of free elements from various diorganyl ditellurides in different solvents and in a microemulsion system. The method is characterized by the use of 59.54 keV γ-rays as a monoenergetic radiation source and the decomposition process is studied through the change in count rate of the characteristic Kα X-ray peak of tellurium in different ditelluride solutions. In the experimental work different aspects have been examined to optimize the sensitivity of the method. It has been found that in coordinating solvents, the rate of decay of dibenzyl ditelluride is much faster in comparison to diphenyl and dipyridyl ditellurides. Moreover, in dibenzyl ditelluride the decay is accompanied with the complete precipitation of elemental tellurium, whereas an adduct is formed by coordination of the solvent molecule with diphenyl/dipyridyl ditelluride. It has also been observed that the methyl substitution in organyl rings makes the ditellurides more stable while the microemulsion system exhibits faster decomposition.

The synthesis of a key branched trisaccharide ( 1 ), of the type IA Group B Streptococcus capsular polysaccharide is described. The monomethyl ether of polyethylene glycol (MeO–(CH 2 CH 2 O) n –H, MPEG) and dioxyxylene [ p -(O)CH 2 –C 6 H 4 –CH 2 (O)–, DOX] have been used as the polymer-support/linker combination. Attempts to use the p -methoxybenzyl (PMB) protecting group under glycosylation conditions involving N -iodosuccinimide/silver trifuoromethanesulfonate promotion resulted in iodination to form the 3-iodo-4-methoxybenzyl (IPMB) derivative. Subsequently IPMB chloride was independently synthesized and used to introduce this new protecting group. The levulinoyl and the IPMB protecting groups have been used in an orthogonal manner to create 3,4-branching on a galactopyranosyl residue. Due to the enhanced acid stability of the IPMB group over the PMB group, the former group was critical to the success of the synthesis. The final trisaccharide and its intermediates were cleaved from the MPEG polymer-support by scandium(III)trifluoromethanesulfonate and acetic anhydride.

The synthesis and characterization of new selenium coronands and of copper(I) and copper(II) complexes of selenium coronands are reported. Molecular structures in the solid state have been determin...

The reagent combination scandium(III) trifluoromethanesulfonate and acetic anhydride efficiently cleaves oligosaccharides bound to the polyethylene glycol (PEG) polymer-support via the dioxyxylene (DOX) linker. Unexpectedly, the site cleavage is between the DOX linker and the PEG polymer. This method of cleavage allows for the use of DOX as a linker for synthesis on polystyrene-polyethylene glycol, PS- PEG beads.

The use of phenyl selenoglycosides as glycosyl donors and acceptors in glycosidation reactions is described. The versatility of these novel compounds is illustrated by the selective activation of both «disarmed» and «armed» phenyl selenoglycoside donors over «armed» ethyl thioglycoside acceptors with silver trifluoromethanesulfonate in the presence of potassium or silver carbonate to give disaccharides in excellent yield. Selective activation of glycosyl bromide donors over phenyl selenoglycoside acceptors is realized by silver trifluoromethanesulfonate promotion in the presence of collidine. Such selectivity is also demonstrated by the activation of a glycosyl trichloroacetimidate donor in the presence of selenoglycoside acceptors with triethylsilyl trifluoromethanesulfonate. The central role of selenoglycosides is illustrated by the synthesis of a trisaccharide that profits from the sequential, selective activation of a glycosyl bromide donor over a selenoglycoside acceptor and the resulting disaccharide selenoglycoside over a thioglycoside acceptor. The liberation of the anomeric hydroxyl group from a phenyl selenoglycoside is also described

The glycosylated building block N α-(fluoren-9-ylmethoxycarbonyl)-N γ-[2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-β-D-glucopyranosyl]-L-asparagine pentafluorophenyl ester 7 has been synthesized and incorporated into the solid-phase synthesis of a panel of peptides and N-linked glycopeptides. These have been synthesized as internally quenched fluorogenic compounds where the position of the glycosylated asparagine residue is sequentially varied. Enzymic hydrolysis of these substrates with Savinase has been followed by fluorescence and the kcat/KM-values have been obtained. It is observed that the glycopeptides are less susceptible to proteolytic degradation than are the corresponding peptides.

[formula: see text] Numerous glycoconjugates contain the disaccharide Neu5Ac alpha (2-->3)DGalp. An efficient way to incorporate this disaccharide into synthetic glycoconjugates is to develop a disaccharide building block. This communication reports a chemoenzymatic route to such a building block which requires as few as four steps. Some examples using more chemical steps are also presented, which increase the flexibility. These disaccharide donors were used to prepare synthetic trisaccharides.

A practical sequence is described for converting d-glucosamine into peracetylated Gal(beta-1,4)GlcNTroc(beta1-S)Ph and Neu5Ac(alpha-2,3)Gal(beta-1,4)GlcNTroc(beta1-S)Ph building blocks using a synthetic strategy based on chemoenzymatic oligosaccharide synthesis. The known trichloroethoxycarbonyl, N-Troc, protecting group was selected as a suitable protecting group for both enzymatic and chemical reaction conditions. These oligosaccharide building blocks proved effective donors for the beta-selective glycosylation of the unreactive OH-3 of a polymeric PEG-bound acceptor and for the axial OH-2 of a mannose acceptor in good yields. The resulting complex oligosaccharides are useful for vaccine and pharmaceutical applications.

[formula: see text] Numerous glycoconjugates contain the disaccharide Neu5Ac alpha (2-->3)DGalp. An efficient way to incorporate this disaccharide into synthetic glycoconjugates is to develop a disaccharide building block. This communication reports a chemoenzymatic route to such a building block which requires as few as four steps. Some examples using more chemical steps are also presented, which increase the flexibility. These disaccharide donors were used to prepare synthetic trisaccharides.

The glycosylated building block N α-(fluoren-9-ylmethoxycarbonyl)-N γ-[2,3,6-tri-O-acetyl-4-O-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-β-D-glucopyranosyl]-L-asparagine pentafluorophenyl ester 7 has been synthesized and incorporated into the solid-phase synthesis of a panel of peptides and N-linked glycopeptides. These have been synthesized as internally quenched fluorogenic compounds where the position of the glycosylated asparagine residue is sequentially varied. Enzymic hydrolysis of these substrates with Savinase has been followed by fluorescence and the kcat/KM-values have been obtained. It is observed that the glycopeptides are less susceptible to proteolytic degradation than are the corresponding peptides.

A panel of α-helical, dimeric coiled-coil peptides has been designed and synthesized for the evaluation of the effect of glycosylation on the conformation of these coiled-coil peptides. Two glycosylated building blocks, Nα -(fluoren-9-ylmethoxycarbonyl)-O-(2,3,4-tri- O-acetyl-6-azido-6-deoxy-β-D -glucopyranosyl)-L-threonine pentafluorophenyl ester 8 and Nα -(fluoren-9-ylmethoxycarbonyl)-O-{2,3,4-tri- O-acetyl-6-[2′-(tert -butoxycarbonylamino)benzoylamino]-6-deoxy-β-D -glucopyranosyl}-L-threonine pentafluorophenyl ester 9 containing the fluorogenic 2-aminobenzamide (Abz) group, have been synthesized. These compounds have been obtained by the glycosylation of Nα-Fmoc-Thr-OPfp with the corresponding glycosyl trichloroacetimidate donors and have been incorporated into the solid-phase synthesis of the peptides 1–3 and 7 and glycopeptides 4–6. Compounds 1 and 4–7 have been synthesized as internally quenched fluorogenic compounds where the Abz group has been employed as the fluorogenic probe and 3-nitrotyrosine Tyr(NO2) as the quenching chromophore. Steady-state fluorescence studies have provided evidence to support the dimerization of the α-helical peptides. Denaturation studies, by fluorescence as well as CD spectroscopy, indicate that the introduction of a carbohydrate moiety into the coiled-coil peptides has a significant destabilizing effect on the α-helicity.